Hua Huilian, Guan Lixia, Pan Bo, Gao Junyi, Geng Yifei, Niu Miao-Miao, Li Zhiqin, Li Jindong
Department of Pharmacy, The Hospital Affiliated to Medical School of Yangzhou University (Taizhou People's Hospital), Taizhou, China.
Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
Front Pharmacol. 2024 Sep 16;15:1454523. doi: 10.3389/fphar.2024.1454523. eCollection 2024.
Overexpression of monopolar spindle 1 (MPS1) and histone deacetylase 8 (HDAC8) is associated with the proliferation of liver cancer cells, so simultaneous inhibition of both MPS1 and HDAC8 could offer a promising therapeutic approach for the treatment of liver cancer. Dual-targeted MPS1/HDAC8 inhibitors have not been reported.
A combined approach of pharmacophore modeling and molecular docking was used to identify potent dual-target inhibitors of MPS1 and HDAC8. Enzyme inhibition assays were performed to evaluate the optimal compound with the strongest inhibitory activity against MPS1 and HDAC8. The selectivity of MPH-5 for MPS1 and HDAC8 was assessed on a panel of 68 kinases and other histone deacetylases. Subsequently, molecular dynamics (MD) simulation verified the binding stability of the optimal compound to MPS1 and HDAC8. Ultimately, cellular assays and antitumor assays evaluated the antitumor efficacy of the most promising compound for the treatment of hepatocellular carcinoma.
Six dual-target compounds (MPHs 1-6) of both MPS1 and HDAC8 were identified from the database using a combined virtual screening protocol. Notably, MPH-5 showed nanomolar inhibitory effect on both MPS1 (IC = 4.52 ± 0.21 nM) and HDAC8 (IC = 6.07 ± 0.37 nM). MD simulation indicated that MPH-5 stably binds to both MPS1 and HDAC8. Importantly, cellular assays revealed that MPH-5 exhibited significant antiproliferative activity against human liver cancer cells, especially HepG2 cells. Moreover, MPH-5 exhibited low toxicity and high efficacy against tumor cells, and it overcomes drug resistance to some extent. In addition, MPH-5 may exert its antitumor effects by downregulating MPS1-driven phosphorylation of histone H3 and upregulating HDAC8-mediated K62 acetylation of PKM2. Furthermore, MPH-5 showed potent inhibition of HepG2 xenograft tumor growth in mice with no apparent toxicity and presented favorable pharmacokinetics.
The study suggests that MPH-5 is a potent, selective, high-efficacy, and low-toxicity antitumor candidate for the treatment of hepatocellular carcinoma.
单极纺锤体1（MPS1）和组蛋白去乙酰化酶8（HDAC8）的过表达与肝癌细胞的增殖相关，因此同时抑制MPS1和HDAC8可能为肝癌治疗提供一种有前景的治疗方法。尚未有双靶点MPS1/HDAC8抑制剂的报道。
采用药效团模型和分子对接相结合的方法来鉴定有效的MPS1和HDAC8双靶点抑制剂。进行酶抑制试验以评估对MPS1和HDAC8具有最强抑制活性的最佳化合物。在一组68种激酶和其他组蛋白去乙酰化酶上评估MPH-5对MPS1和HDAC8的选择性。随后，分子动力学（MD）模拟验证了最佳化合物与MPS1和HDAC8的结合稳定性。最终，细胞试验和抗肿瘤试验评估了最有前景的化合物对肝细胞癌的治疗效果。
使用组合虚拟筛选方案从数据库中鉴定出六种MPS1和HDAC8的双靶点化合物（MPHs 1-6）。值得注意的是，MPH-5对MPS1（IC = 4.52±0.21 nM）和HDAC8（IC = 6.07±0.37 nM）均表现出纳摩尔级的抑制作用。MD模拟表明MPH-5与MPS1和HDAC8均稳定结合。重要的是，细胞试验表明MPH-5对人肝癌细胞，尤其是HepG2细胞表现出显著的抗增殖活性。此外，MPH-5对肿瘤细胞表现出低毒性和高效性，并且在一定程度上克服了耐药性。此外，MPH-5可能通过下调MPS1驱动的组蛋白H3磷酸化和上调HDAC8介导的PKM2的K（62）乙酰化来发挥其抗肿瘤作用。此外，MPH-5对小鼠HepG2异种移植瘤生长具有强效抑制作用，且无明显毒性，并呈现出良好的药代动力学特性。
该研究表明MPH-5是一种用于治疗肝细胞癌高效、选择性强、低毒的抗肿瘤候选药物。
